Complement system is the main component of innate immunity; it's also an important modulator of adaptive immunity, which plays an important role in immune surveillance. It can not only remove the pathogenic bacteria and host cell debris invaded, but also coordinate the entire immunological and inflammatory process. The complement system can be activated by three ways: the classical pathway (CP), the alternative pathway (AP) and the lectin pathway (LP), it plays physiological function mainly through the products formed after the activation. The pathways include that the C3b/iC3b deposited on the membrane surface of the cells being attacked, recruiting immune effectors' cells such as mononuclear cells to eliminates the target cells by phagocytosis; anaphylatoxins such as C3a/C4a/C5a cause local inflammation; and the membrane attack complex (Membrane Attack Complex, MAC, that is C5b-9n) assembles poles on the surface of the target cell membrane and ultimately leading to cell lysis and death.
In order to prevent the “by-stander injury” effects of complement activation to the normal host cells in the process, the host has evolved more than 10 regulatory proteins, including circulatory C1-INH (C1 inhibitor), C4BP (C4 binding protein), factor I, factor H, S-protein, clusterin, and membrane-bound protein CD35/CR1, CD46/MCP, CD55/DAF, CD59 expressed on the surface of the cell membrane, and another complement membrane regulatory protein CRIg found in the near future.
CRIg was initially identified as C3b/iC3b receptor expressed on the surface of liver macrophage (Kupffer's cell). Through CRIg binding to C3b/iC3b, Kupffer's cells can phagocytize pathogen or other particles. The result of crystal structure study demonstrated that through specific binding to C3b/iC3b and subsequent inhibition of C3 convertase, CRIg can inhibit complement activation via alternative pathway at the early stage with a lower efficacy in compared with the canonical complement inhibitor on alternative pathway, factor H. Until now, there is no any report to develop the targeted complement inhibitor by utilizing the unique feature of CRIg binding to C3b/iC3b.
The versatile functions of the complement system are able to be finely tuned to establish a delicate balance between activation and inhibition but the tipping of this delicate balance has been attributed to initiation, progression and treatment of various human disorders.
Numerous studies have demonstrated that the excessive complement activation contributes, at varying degree, to the occurrence and progression of various human diseases, such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, aplastic anemia, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, atherosclerosis, Parkinson's disease, Alzheimer's disease (senile dementia), asthma, allergy, psoriasis, myasthenia Gravis, multiple emitting hardening, clone's bowel disease. Therefore, the drug research and development of complement as the therapeutic target, including inhibitors of complement system renewed attention. The complement system inhibitors, especially the complement-targeted therapeutics holds great potential with social and economic value.
After decades of investigation for the research and development of complement targeting inhibitor, including the protein Compastatin combined with C3 and the recombinant monoclonal antibody Eculizumab against C5 (Soliris, Alexion Pharmaceuticals), both have some obvious deficiencies. Compastatin has entered the pre-clinical trials, however, it inhibits C3 function of all parts thus leads to a potential risk of infection.
Eculizumab has been used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), but its intellectual property ownership belongs to foreign countries and it has an extremely high price, with a single year of treatment costing $409,500. The annual sales of Soliris in 2009 and 2010 are $ 2.95 and 5.41 billion US dollar.
PNH is an acquired hemorrhagic disease due to PIG-A mutation, thus resulting in the absence of two glycosylphosphatidylinositol (GPI)-anchored complement membrane regulatory proteins CD55 and CD59 on blood cell membrane. Therefore, the PNH blood cells are very susceptible to complement attack, and prone to infection caused by leukocyte decrease, hemolysis caused by hemocytocatheresis, and platelet activation. It eventually leads to repeated infection, haemolytical, thrombosis, renal failure, bone marrow failure and the lung moves venous pressure rise and other disease. These diseases getting worse progressively are no cure before the occurrence of Eculizumab monoclonal antibody, which seriously threaten the patients' life. The mechanism of Eculizumab is through binding to C5 and inhibiting complement activation at the end of the complement cascade, subsequently blocking MAC deposition on the membrane of blood cells and the lysis of blood cells especially red blood cells, the Eculizumab has a good effect in clinical treatment of patients with PNH, and can significantly reduce thrombosis. With a single year of treatment, 66% PNH patients can stop blood transfusion.
However, the PNH patient's condition is still not complete remission after the application of Eculizumab monoclonal antibody theoretically, because the level of C3 complement cascade activation persists, and leads to the generation of C3b/iC3b and their deposition on the surface of blood cells, making these blood cells consumed by mononuclear cells phagocytosis, eventually leading to the extravascular hemolysis. This is also the reason that Eculizumab treatment is not very satisfactory. Therefore, to prevent the activation of complement on the C3 level in the early activation of complement instead of the C5 level at the end of Eculizumab, can significantly reduce both the MAC mediated intravascular hemolysis and C3b/iC3b mediated extravascular hemolysis, thus get better therapy efficiency.